This invention provides a process for the preparation of 3- and/or 6-substituted 2,5-morpholinediones represented by Formula I where each R is independently H, C.sub.1 -C.sub.12 hydrocarbyl or C.sub.1 -C.sub.12 substituted hydrocarbyl and at least one R is C.sub.1 -C.sub.12 hydrocarbyl or C.sub.1 -C.sub.12 substituted hydrocarbyl. ##STR1## Compounds of Formula I are useful as precursors for the preparation of depsipeptide polymers and copolymers. Depsipeptides are cyclic polypeptides in which some amide nitrogens are replaced with oxygen. Ring-opening polymerizations or copolymerizations of 2,5-morpholinedione derivatives give polydepsipeptides of high molecular weight. These degradable polymers are particularly useful for applications where programmed lifetime of the polymer product is desirable. For example, applications include, but are not limited to, bioabsorbable medical implant devices such as sutures.
2,5-Morpholinedione derivatives have been prepared from N-(.alpha.-haloacyl)-.alpha.-amino acid salts. Chadwick and Pacsu obtained 6-methyl-2,5-morpholinedione by sublimation from alkaloid and sodium salts of (.alpha.-bromopropionylglycine (J. Am. Chem. Soc. 65, 392 (1943)). Similarly, Cook and Cox prepared various 2,5-morpholinedione derivatives with alkyl substituents at the 3-, 4- and/or 6-positions (J. Chem. Soc., 2347 (1949)). More recently, unsubstituted and 3-, 4- and/or 6-alkyl substituted 2,5-morpholinediones, suitable for polymerization, have been prepared from the appropriate N-(.alpha.-haloacyl)-.alpha.-amino acid salts by sublimation from the heated salt (Shalably and Koelmel, U.S. Pat. No. 4,441,496, Heider et al., Makrotool. Chem., Rapid Commun. 6, 9 (1985), Yonezawa et al., Makromol. Chem., Rapid Commun. 6, 607 (1985), in't Veld et al., Makromol. Chem. 191, 1813 (1990)) or by reaction in solution (Fung and Glowaky, U.S. Pat. No. 4,916,209 (EP 322154;1989) ). Rumsch et al. prepared (L)-3-phenylmethyl-2,5-morpholinedione by treating N-bromoacetyl-(L)-phenylalanine with silver oxide in dioxane (FEBS Letters 9, 64 (1970)).
Obrecht and Heimgartner prepared diamides of Formula II (where R.sup.1 =H, methyl, phenylmethyl, or phenyl) from .alpha.-hydroxy carboxylic acids and 3-(dimethylamino)-2,2-dimethyl-2H-azirine which when treated in solution with HCl gave 6,6-dimethyl-, 6-phenylmethyl-, and 6-phenyl- (but not 6,6-diphenyl-) derivatives of 3,3-dimethyl-2,5-morpholinedidone (Helv. Chim. Acta 70, 329 (1987)). ##STR2##
3,6-Disubstituted 2,5-morpholinediones were prepared by treating a chloroform/toluene solution of N-(.alpha.-hydroxyacyl) amino acids with methanesulfonic acid in a Soxhlet apparatus containing 3A molecular sieves (Hartwig and Schollkopf, Liebigs Ann. Chem., 1952 (1982)).
2,5-Morpholinediones derivatives have also been prepared from O-(.alpha.-aminoacyl)-.alpha.-hydroxy carboxylic acid derivatives of Formula III where R.sup.2 =H or alkyl and C(O)X corresponds to the N-hydroxysuccinimide ester, pentachlorophenyl ester, acid azide, or acid chloride (Ridge et al., J. Chem Soc., Perkin I, 2041 (1972); Nissen et al., Makromol. Chem., Suppl. 1, 23 (1975); Yasutake et al., FEBS Letters 100, 241 (1979); and Shemyakin et al., Zh. Obshch. Khim 42, 2320 (1972)). ##STR3## In each case, the compounds of Formula III were obtained by condensation of N-protected amino acids (e.g., benzyloxycarbonyl) with .alpha.-hydroxy carboxylic acid derivatives followed by a deprotection step.
The processes described above may be used in the preparations of 3- and/or 6- substituted 2,5-morpholinediones, however, they require time consuming substrate preparation and costly purification procedures in order to recover pure product.